Although obesity is becoming a serious social problem in modern society, the effects of existing obesity therapeutic drugs (such as Orlistat, Dexfenfluramine, Sibutramine or Phentermine) are not always adequate while also having problems relating to adverse side effects.
Obesity causes numerous health problems either by itself or in correlation with other diseases. Examples of life-threatening diseases associated with obesity include hypertension, type 2 diabetes, hyperinsulinemia, insulin resistance, dyslipidemia, hyperlipidemia, arteriosclerosis and heart disease.
Among these, there is an intimate relationship between type 2 diabetes and obesity.
Examples of causative factors of type 2 diabetes include impaired pancreatic insulin secretion and insulin resistance. Hypertrophy of fat tissue in obesity not only decreases the number of insulin receptors of fat cells, but also accelerates the secretion of insulin resistance-inducing cytokines such as TNF-α from fat cells, thereby causing insulin resistance.
Thus, prevention of obesity is important for type 2 diabetes patients and persons at risk thereto, and alleviation of obesity is strongly required in type 2 diabetes patients with obesity in combination.
On the other hand, dipeptidyl peptidase 4 (DPP4) is a type of serine protease that specifically hydrolyzes a dipeptide of Xaa-Pro or Xaa-Ala (wherein Xaa may be any amino acid) from the N terminal of a polypeptide chain.
GLP-1 (glucagon-like peptide 1) is a peptide hormone that mainly has the augmented action in glucose-stimulated insulin secretion, is primarily secreted from the lower small intestine after meals, and acts in the pancreas. DPP4 deactivates this GLP-1 by hydrolyzing it, as well as DPP4 causes the production of peptides that act as antagonists of GLP-1 receptors.
Compounds that inhibit the enzyme activity of DPP4 (DPP4 inhibitors) enhance glucose-stimulated insulin secretion by enhancing the action of intrinsic GLP-1 by means of this inhibitory action, thereby demonstrating blood sugar lowering action, while improving impaired glucose tolerance.
Consequently, DPP4 inhibitors are considered to be useful in the prevention and treatment of such diseases as diabetes, and numerous DPP4 inhibitors have been developed as therapeutic drugs for diabetes (in particular type 2 diabetes) (Augustyns, et al., Expert Opin. Ther. Patents, 2003, 13: 499-510; Campbell, Ann. Pharmacother., 2007, 41:51-60).
Analogues of GLP-1 have also been developed as therapeutic drugs for diabetes. In addition, there are also reports suggesting that GLP-1 has an anorexic action. For analogues of GLP-1, reports have been observed indicating that anti-obesity effects have been obtained in clinical studies in humans (Zander, et al., Lancet, 2002, 359:824-830; Iltz, J. L., et al., Clin. Ther., 2006, 28(5):652-65; Mack, et al., Int. J. Obes., 2006, 30(9):1332-40; DeFronzo, et al., Diabetes Care, 2005, 28(5):1092-100).
Although DPP4 inhibitors are expected to demonstrate effects in the treatment or prevention of obesity and the like, there has been no preclinical or clinical reports so far indicating that significant anti-obesity effects were obtained by administration of DPP4 inhibitors alone.
The following is known with respect to saccharides.
Various saccharides are known to cause a rise in GLP-1 levels. In addition, several saccharides are known to inhibit weight gain by administration thereof.
For example, a publication by Shima, et al. (Acta Endocrinologica, 1990, 123:464-470) discloses that blood GLP-1 levels are increased following administration of saccharides such as D-glucose, D-galactose, maltose, sucrose or maltitol.
A publication by Tokunaga, et al. (J. Nutri. Sci. Vitaminol., 1986, 32:111-121) and Japanese Examined Patent Publication No. S62-60369 disclose that inhibition of weight gain is observed by administration of fructooligosaccharide to rats.
Publications by Cani, et al. disclose that administration of oligofructose (Raftilose; mixture of glucosyl-(fructosyl) n-fructose and (fructosyl) m-fructose; average degree of polymerization: 4.5) to rats or mice increases GLP-1 concentration in blood and intestine, decreases blood sugar levels during glucose loading, and demonstrates effects on reducing body weight in high fat diet-fed rats etc. (Cani, et al., British Journal of Nutrition, 2004, 92:521-526; Cani, et al., Obesity, 2005, 13:1000-1007; Cani, et al. Journal of Endocrinology, 2005, 185:457-465; Cani, et al., Diabetes, 2006, 55:1484-1490; and WO 2005/36990).
Japanese Unexamined Patent Publication No. H6-65080 discloses a health food for preventing obesity that contains L-arabinose, D-xylose and the like, and that administration of L-arabinose inhibited weight gain in mice.
Japanese Unexamined Patent Publication No. H10-290681 discloses an anti-obesity agent and/or body fat mass reducing agent and the like having a xylooligosaccharide as an active ingredient thereof.
However, the combined use of a DPP4 inhibitor with a sweetener such as a saccharide for the purpose of anti-obesity effects is not known.
Patent Document 1: Japanese Examined Patent Publication No. S62-60369
Patent Document 2: Japanese Unexamined Patent Publication No. H6-65080
Patent Document 3: Japanese Unexamined Patent Publication No. H10-290681
Patent Document 4: International Patent Publication No. WO2005/36990
Non-Patent Document 1: Augustyns, et al., Expert Opin. Ther. Patents, 2003, 13: 499-510
Non-Patent Document 2: Campbell, Ann. Pharmacother., 2007, 41:51-60
Non-Patent Document 3: Zander, et al., Lancet, 2002, 359:824-830
Non-Patent Document 4: Iltz, J. L., et al., Clin. Ther., 2006, 28(5):652-65
Non-Patent Document 5: Mack, et al., Int. J. Obes., 2006, 30(9):1332-40
Non-Patent Document 6: DeFronzo, et al., Diabetes Care, 2005, 28(5):1092-100
Non-Patent Document 7: Shima, et al., Acta Endocrinologica, 1990, 123:464-470
Non-Patent Document 8: Tokunaga, et al., J. Nutri. Sci. Vitaminol., 1986, 32:111-121
Non-Patent Document 9: Cani, et al., British Journal of Nutrition, 2004, 92:521-526
Non-Patent Document 10: Cani, et al., Obesity, 2005, 13:1000-1007
Non-Patent Document 11: Cani, et al. Journal of Endocrinology, 2005, 185:457-465
Non-Patent Document 12: Cani, et al., Diabetes, 2006, 55:1484-1490